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Model suggests physiologic changes with
aging underlie ritonavir PK shifts
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20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
Physiologically based pharmacokinetic (PBPK) modeling determined that age-related PK changes with ritonavir lie in the same range as non-HIV drugs [1]. A Basel-Liverpool team believes that suggests age-related ritonavir changes mainly reflect physiologic changes like decreasing liver weight and waning liver and kidney blood flow.
The researchers noted that PK analyses of antiretrovirals and comedications are not keeping up with the longer life expectancy of people with HIV and their growing use of multiple medications as they age. As a result, the Basel-Liverpool group observed, whether aging populations need dose adjustments remains uncertain. To address these issues, they built a PBPK model to perform virtual clinical trials in an aging population.
Researchers generated a virtual population of 20- to 99-year-olds with age-dependent physiologic changes. They used that population to inform a whole-body PBPK model and picked ritonavir as a proof-of-concept drug because ritonavir PK data are available in aging people with HIV and could verify the model [2]. The validated PBPK model simulated age-dependent changes in ritonavir PKs throughout adulthood in 16 age groups of 500 virtual individuals, half of them women, across ages 20 to 99. The investigators normalized PK parameters to the youngest age group, 20 to 24.
Simulations of ritonavir area under the concentration-time curve (AUC) with a boosting dose of 100 mg daily correctly predicted clinically observed data in young adults (20 to 50 years), a middle-aged group (55 to 60 years) and an elderly group (65 to 85 years). AUC elderly/young ratios were similar for observed data (1.25), in the 55-to-60 group (1.25), and in the 65-to-85 group (1.55).
While maximum concentration, time to maximum concentration, and volume of distribution did not change with age, AUC rose 1.5% per year of age and terminal half-life rose 1.0% per year. As a result, ritonavir clearance fell by a maximum 2-fold difference compared with the youngest age group. From age 55 onward, age-related changes exceeded what would be expected from interindividual variability (1.25-fold). Age-related PK changes did not differ by gender.
The researchers concluded that "changes in ritonavir exposure with age are driven by physiological changes impacting drug elimination such as the reduction in liver mass and decreased hepatic and renal blood flow." They noted that simulated age-related changes in ritonavir PKs reflect those seen with non-HIV drugs. As a result, the researchers proposed, the ritonavir findings "might be extrapolated to other antiretrovirals."
References
1. Stader F, Kinvig H, Penny M, et al. Physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure changes in aging people living with HIV. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 15.
2. Dumond JB, Adams JL, Prince HM, et al. Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study. HIV Med. 2013;14:401-409. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664258/
20th Intnl Wrkshp Clin Pharm: Physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure changes in aging people living with HIV- (05/16/19)
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